The Clinical Immunotherapy Program is a highly interactive research effort that has a rich history of bringing targets discovered in the laboratory through preclinical models into early stage clinical trials with the goal of selecting experimental therapies for late stage clinical testing. The present proposal continues this tradition through targeting tissue-specific antigens for cancer therapy using antigen receptors. The rationale is based on the remarkable specificity of the antigen receptors on T cells and B cells. Shared themes include targeting differentiation antigens and tumor stroma, specificity of antigen receptors, enhancement of potency of antigen receptor-based therapies, modulation of immunity, overcoming heterogeneity in the tumor, and the application of sophisticated methods for imaging and quantitation. Two strategies for therapy are explored active immunotherapy (vaccines) to generate antibody and T-cell responses and passive immunotherapy with antibodies (monoclonal antibodies, mAb). The Program has four projects that use new approaches (e.g., single chain Fv mAb fragments, alpha emitters, nanogenerators, optical imaging, heteroclitic DNA vaccines, T-cell homeostasis for vaccination) for: 1) Increasing antibody potency by arming with alpha particle emitters with extraordinary energy over a very short range. 2) Overcoming limitations of targeting antibodies to solid tumors using novel miniaturized antigen-binding domains of antibodies to penetrate tumors more effectively. 3) Overcoming tolerance against tissue-specific self antigens in cancers for active immunization by increasing potency through rationally designed antigen mutants to enhance antigen presentation. 4) Enhancing and skewing immune responses toward tumor antigens following active immunization during recovery of immune homeostasis after bone marrow ablation. An Administrative Core provides biostatistics, data management, nursing, and pharmacy support. The Biophysics and Nuclear Medicine Core provides state-of-the-art optical and nuclear imaging, dosimetry, radiochemistry, and advanced molecular imaging. The Immune Monitoring Core measures cytokines, antibodies and T-cells, including quantitation, specificities and phenotype. The ultimate goal is to establish new principles and strategies for antigen receptor-based therapies, and more specifically develop synergistic treatments that combine antibodies and T cells directed at different and overlapping cellular and tissue compartments.